This invention is a single-pot process for trialkylsilyl trifluoromethanesulfonate (R.sub.3 Si--OTf) mediated production of derivatives of 4-aza 3-keto steroids at the .alpha.-methylenic carbon through electrophilic substitution. These derivatives are useful in the preparation, through elimination of the substituent on the .alpha.-methylene carbon, of the .DELTA.-1 olefin 4-aza 3-keto steroids which are potent inhibitors of 5-.alpha. reductase.
The enzyme, 5-.alpha. reductase, is responsible for the local formation within a target organ of 5.alpha.-dihydrotestosterone, which is the principal mediator of androgenic activity in some organs.
Inhibitors of testosterone-5.alpha.-reductase have been shown to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfe et al., [Steroids, 14, 269 (1969)] demonstrated in vitro that methyl 4-androsten-3-one-17.beta.-carboxylate was a testosterone-5.alpha.-reductase inhibitor. Voigt and Hsia, [Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692], demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17.beta.-carboxylic acid are both active inhibitors of testosterone-5.alpha.-reductase in vitro.
Topical application of either testosterone or 5.alpha.-dihydrotesterone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concomitant administration of 4-androsten-3-one-17.beta.-carboxylic acid, or its methyl ester, inhibited the response elicited by testosterone but did not inhibit the response elicited by 5.alpha.-dihydrotestosterone. These results indicated that the compounds are antiandrogenic by virtue of their ability to inhibit testosterone-5.alpha.-reductase.
A number of 4-azasteroid compounds are known. See, for example, U.S. Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat. No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm. Sci., 60 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition, U.S. Pat. Nos. 4,377,584 and 4,220,775 of Rasmusson et al., described a group of 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which are said to be useful in the treatment of hyperandrogenic conditions. Furthermore, in U.S. Pat. Nos. 4,760,071, Rasmusson et al., disclosed novel 17.beta.N-(monosubstituted) carbamoyl-4-aza-5.alpha.-androst-1-ene-3-ones, which are highly potent testosterone-5.alpha.-reductase inhibitors.
The processes known in the art for preparing the aforementioned compounds generally include a step wherein a double bond is introduced into the lactam ring of the azasteroid. Thus, selenic anhydride oxidation [Back, T. G., J. Org. Chem., 46, 1442 (1981)], sulfoxide elimination [U.S. Pat. No. 4,377,584; 4,220,775], and silylation mediated DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) oxidation have all been used heretofore for the introduction of the .DELTA.-1 olefin functionality.
The instant invention discloses a method whereby a powerful silylating reagent mediates regiospecific electrophilic substitution on the lactam ring to produce a versatile array of azasteroid derivatives substituted at the .alpha.-methylenic carbon. These derivatives are useful, through elimination of the added substituents, for making the .DELTA..sup.1 -olefin azasteroid derivative having potent 5-.alpha. reductase inhibitory activity.